Patients with hyperlipidemia or diabetes are estimated currently as 10 million or more in total in our country, and the number has been steadily increasing. Many of patients with diabetes suffer from non-insulin dependent diabetes mellitus, which is characterized by a pathological condition presenting hyperglycemia is resistant to the insulin action. Further, symptoms such as hyperinsulinemia, hypo HDL cholesterolemia, hypertension, and obesity most frequently occur with hyperlipidemia and diabetes, which raises clinical problems. In recent years, such pathological conditions presenting these multiple symptoms are referred to as Syndrome X, and considered as one of severe diseases (Reference: Diabetes, 37, 1595-1607 (1988)).
As medicaments for therapeutic treatment of these diseases, clofibrate derivatives including clofibrate as a typical example, thiazolidine derivatives including pioglitazone and troglitazone as typical examples and the like have been used. The clofibrate derivatives have an activating action on PPAR α (Reference: Nature, 347, 645-650 (1990)) and are considered to improve lipid metabolism through the aid of fatty acid β-oxidation enzymes in the liver. The thiazolidine derivatives have an activating action on PPAR γ (Reference: J. Biol. Chem., 270, 112953-112956 (1995)) and are considered to ameliorate insulin resistance and thereby lower a blood sugar level (Reference: Diabetes, 45, 1661-1669 (1996)).
However, PPAR agonists are reported to generally have adverse effects such as liver function failure, and accordingly, a patient with liver function failure. contraindicates the use of troglitazone, one of the PPAR γ agonists (Reference: Rinsho Iyaku, 14, 461-466 (1998)), and the sale of said drug was currently discontinued.
As described above, medicaments having the PPAR activation activity are useful as therapeutic agents for hyperlipidemia and diabetes. However, since they have various adverse effects, medicaments activating PPAR have been desired which have reduced adverse effects.
(2E,4E,6E,10E)-3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapentaenoic acid (Development Code: “NIK-333”), one of polyprenyl compounds, is known to have affinities for retinoic acid binding proteins and retinoic acid receptors and to have actions of inducing differentiation and apoptosis in hepatocellular carcinoma. Clinically, NIK-333 significantly inhibited recurrence of hepatoma after radical treatment of hepatoma by long-term administration for one-year, and thus its action of suppressing recurrence of hepatoma was suggested. Further, NIK-333 is proved to be a safe drug, because almost no liver function failure or almost no other adverse effect, generally accompanied with retinoids, was observed during the administration (Reference: N. Eng. J. Med., 334, 1561-1567 (1996)).
However, it his not been known that a polyprenyl compound activates PPAR.